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Saturday, December 31, 2005

Gastroesophageal reflux disease is a chronic disorder that requires long-term therapy in most patients. The appropriate medical therapy should be individualized to the severity of symptoms, the degree of esophagitist and the presence of other acid-reflux complications. Lifestyle changes should form the basis of any therapeutic approach. In patients with mild to moderate disease, initial therapy with histamine [H.sub.2]-receptor antagonists in conventional dosages is suggested. Prokinetic agents are potentially useful in patients with impaired esophageal or gastric motor function, but their efficacy as single agents does not appear to surpass that of standard doses of [H.sub.2] blockers. Sucralfate, a cytoprotective agent, is an additional therapeutic option. For patients with more severe disease, omeprazole and lansoprazole provide unequaled healing rates and accelerated symptom relief. In most patients, maintenance therapy is vital. Surgery is indicated in patients whose disease is refractory to medical therapy and in those who develop complications not amenable to medical therapy.

The phrase "gastroesophageal reflux disease" denotes abnormal acid exposure of the esophagus, which leads to reflux esophagitis.[1] The degree of damage to the esophageal mucosa correlates with the extent of acid and pepsin exposure, as measured by prolonged intraesophageal monitoring with a pH probe. Increased acid clearance time, decreased mucosal resistance and delayed gastric emptying, as well as hiatal hernia and reflux of alkaline fluid, appear to be involved in the pathogenesis of esophagitis. However, the most common mechanism thought to underlie reflux episodes is transient lower esophageal sphincter (LES) relaxation, an abrupt reduction in LES pressure that is not precipitated by swallowing.[2]

Both traditional and newer therapies have, for the most part, focused on reducing esophageal acid exposure by inhibiting or neutralizing acid secretion and improving LES pressure and esophageal clearance.[3-7] The healing rate, successful achievement of complete healing and maintenance of remission are clearly correlated with limited acid exposure.[8]

Phase 1 Medical Therapy

Traditional "phase 1" medical therapy for reflux esophagitis includes postural methods (remaining upright following meals and at bedtime), avoidance of tight-fitting garments, weight loss if appropriate, modifications in dietary habits (avoiding large meals and foods that lower LES pressure, such as fats, chocolate and coffee), cessation of smoking and alcohol use, and avoidance of drugs that reduce LES tone, such as theophylline, calcium channel blockers and anticholinergic agents.[9] A recent report suggested relaxation training as an adjunct to antireflux therapy in patients who experience increased symptoms during times of stress.[10] Table 1 summarizes the nonpharmacologic treatment of gastroesophageal reflux disease.

Although antacids are the most commonly used agents in the treatment of reflux symptoms, evidence of significant symptomatic or endoscopic improvement with these agents is lacking. Gaviscon, an alginic acid-antacid combination, has been reported to provide better symptom relief than antacids alone.[11]

Although antacids are appropriate for occasional symptomatic relief, they are inadequate therapy for frequent esophagitis symptoms. Antacids have a short duration of action (secondary to rapid clearance from the esophagus and transient neutralization of gastric acid) and no effect on nocturnal acid secretion. Over-the counter histamine [H.sub.2]-receptor antagonists (Table 2) are a recent addition to phase 1 medical therapy. The impact of these drugs on patients' medical care-seeking behavior is unknown.

[TABULAR DATA 2 OMITTED]

Phase 2 Medical Therapy

In this article, it is assumed that the diagnosis of gastroesophageal reflux disease has been secured through esophagogastroduodenoscopy (EGD), pH monitoring or other measures. Although empiric therapy may be used in patients with the typical symptoms of uncomplicated gastroesophageal reflux disease, the diagnosis should be confirmed if symptoms are persistent or refractory.

[H.sub.2] BLOCKERS

Patients with significant symptoms of gastroesophageal reflux disease are usually treated with a course of continuous "phase 2" medications, which typically include an [H.sub.2] blocker, with or without prokinetic agents (Figure 1). [H.sub.2] blockers reduce esophageal acid exposure by reducing gastric acid secretion and volume. Conventional dosages of [H.sub.2] blockers generally inhibit 60 to 70 percent of 24-hour acid secretion.(12)

Substantial evidence suggests that [H.sub.2] blocker therapy alleviates reflux symptoms in many patients and promotes healing of mild to moderate erosive esophagitis. Studies show that the therapeutic response depends primarily on the endoscopically determined grade or severity of the esophagitis and only secondarily on the duration of therapy.[13] Healing frequencies with cimetidine (Tagamet), totaling 800 to 1,600 mg daily in divided doses for six weeks, are typically 50 to 70 percent for minimal esophagitis but drop to 20 to 30 percent for circumferential erosions.[14] When treatment is extended to 12 weeks, healing rates increase to 80 to 90 percent and 40 to 50 percent, respectively, in most studies.

Comparable results are reported from most studies assessing equipotent dosages of the other [H.sub.2] blockers--ranitidine (Zantac), famotidine (Pepcid) and nizatidine (Axid)--for gastroesophageal reflux disease. Double-blind, randomized comparisons between these "standard-dose" regimens of the [H.sub.2] blockers are limited but do not demonstrate significant statistical differences in therapeutic outcome.

Most studies with [H.sub.2] blockers evaluate divided-dose regimens to inhibit both daytime and nocturnal acid secretion. Many patients experience daytime symptoms so predominantly that, theoretically, they would not be responsive to nocturnal administration of [H.sub.2] blockers. However, nocturnal acid reflux is more predictive of gastroesophageal reflux disease complications than daytime acid exposure, emphasizing that patients with severe disease need nocturnal medication despite predominantly daytime symptoms.

PROKINETIC AGENTS

Prokinetic drugs potentially reduce gastroesophageal reflux by two mechanisms: (1) increasing LES pressure and (2) accelerating gastric emptying. They also facilitate acid clearance from the esophagus by enhancing esophageal peristalsis.[15] Agents presently available in generic form include bethanechol (Urecholine), a cholinergic agonist, and metoclopramide (Reglan), a dopamine antagonist and cholinergic agonist. The effects actually produced by these drugs, however, appear to be limited. Although both agents enhance LES pressure, patients with the lowest resting pressure have the smallest increase in sphincter tone. Bethanechol does not appear to accelerate gastric emptying, and metoclopramide does not clearly improve esophageal acid clearance. The clinical efficacy of bethanechol and metoclopramide in the treatment of gastroesophageal reflux disease has not been consistently confirmed.

Bethanechol plus antacids has been shown to be more effective than antacid therapy alone in one of two studies.[16] Although metoclopramide at a dosage of 10 mg four times daily has reportedly improved reflux symptoms in two out of four studies, 24-hour acid contact time within the esophagus is not diminished with this dosage.[16]

Studies comparing bethanechol or metoclopramide with standard doses of [H.sub.2] blockers have demonstrated clinical outcomes equal to or less effective than outcomes with prokinetic agents.[17] Their unimpressive results, especially in promoting healing of erosive esophagitis, are compounded by the appreciable toxicity, including extrapyramidal reactions, of metoclopramide.[18]

Cisapride (Propulsid) has the broadest spectrum of action of the prokinetic drugs. Cisapride enhances the release of acetylcholine from postganglionic nerve endings in the myenteric plexus and is a serotonin type IV-receptor agonist. Several placebo-controlled studies have shown that cisapride alleviates reflux symptoms and promotes esophageal healing.[19] In direct comparative studies, cisapride is as effective as standard doses of cimetidine or ranitidine and is somewhat better than metoclopramide.[15] In addition, the side effect profile of cisapride is low; this drug should serve as the first choice among promotility agents. Erythromycin, in either low dosages (250 mg four times daily) or high dosages (500 mg four times daily), has little effect on acid exposure time and thus appears to have no important clinical role in therapy for gastroesophageal reflux disease.[20]

SUCRALFATE

Sucralfate (Carafate) is a sulfated disaccharide complex with aluminum hydroxide that has a minimal buffering effect in the stomach and does not appreciably alter gastric acid or pepsin secretion. It adheres to damaged tissue during its passage through the esophagus with swallowing and after reflux of gastric content. Sucralfate is most often given in dosages of 1 g four times daily. Some studies have reported no significant benefit of sucralfate suspension over placebo for symptom relief or healing. Other studies, however, have found short-term healing rates in mild-to-moderate esophagitis to be comparable to rates with standard dosages of cimetidine or ranitidine.[21]

COMBINATION MEDICAL THERAPY

Combining conventional antisecretory dosages of [H.sub.2] blockers with prokinetic agents does not necessarily enhance the clinical response achieved by monotherapy. Combination therapy with metoclopramide and cimetidine resulted in statistically significant (although clinically modest) enhancement of endoscopic healing (55 percent versus 42 percent) in one of two reports.[22] Cisapride has also been shown to significantly enhance the response to cimetidine alone.[23] However, combination therapy with sucralfate, 1 g three times daily, and cimetidine, 400 mg at night, provided no advantage over sucralfate at 1 g four times daily.[24]

Cimetidine, 300 mg four times daily, plus sucralfate, 1 g after meals and 2 g at bedtime, improved the endoscopically determined outcome of esophagitis more frequently than cimetidine alone, although fewer than 50 percent of patients in either group showed endoscopic improvement after 12 weeks, and total healing rates were not different.[25] Sucralfate, 1 g after meals, with ranitidine, 300 mg after dinner, was no better than sucralfate alone and produced complete healing in only,31 percent of patients after 16 weeks.[26]

Medical Therapy for Severe/Refractory Gastroesophageal Reflux Disease

In patients with severe esophagitis, healing rates of less than 50 percent have been reported with conventional [H.sub.2] blocker regimens of eight to 12 weeks.[13] Recently, several authors have reported that many of these patients tend to have higher basal acid outputs and more severe pretreatment amounts of acid reflux, and exhibit no or poor inhibition of gastric acid secretion with standard or higher dosages of [H.sub.2] blockers (i.e., ranitidine at 150 to 300 mg twice daily).[8,27] High dosages of ranitidine (up to 3,000 mg daily) were required to normalize esophageal acid exposure and promote endoscopic healing in this patient group.[28] Symptom relief and healing were achieved after the ranitidine was titrated to inhibit the basal acid output to less than 1 mEq per hour.[8,23]

Profound acid suppression has also been reported with proton pump inhibitors. Omeprazole (Prilosec) is the first drug of this class to be marketed. The drug irreversibly and noncompetitively inactivates parietal cell [H.sup.+]-[K.sup.+]-ATPase, the gastric proton pump located in the secretory apparatus of the parietal cell membrane. Omeprazole inhibits both basal and stimulated acid secretion. In most patients, a single daily dose of 20 to 30 mg inhibits 24-hour acid secretion by better than 90 percent. Compared with standard dosages of [H.sub.2] blockers with or without metoclopramide, an eight-week course of omeprazole, at 20 to 60 mg daily, produces more complete and longer-lasting acid suppression (thus normalizing esophageal acid exposure) and achieves superior rates of healing of erosive esophagitis (better than 71 percent).[29] Furthermore, patients with esophagitis refractory to more than 12 weeks' high-dose therapy with cimetidine (3.2 g daily) or ranitidine (300 to 900 mg daily) heal 92 percent of the time after 12 weeks' therapy with 40 mg daily of omeprazole.[30,31] Omeprazole at 40 mg daily produces slightly faster endoscopic healing rates than a dosage of 20 mg daily; however, overall healing at each dosage is equivalent to prolonged therapy (up to 12 weeks) in large study populations.[32] Therefore, initial therapy with 20 mg daily for at least four weeks is appropriate before resorting to higher dosages.[33]

Occasionally, patients are refractory to omeprazole therapy and demonstrate persistent esophageal acid exposure. This occurrence has been attributed to either an unusually short duration of gastric acid inhibition or a virtually absent inhibitory response to omeprazole as assessed by intragastric pH monitoring.[31] In selected persons, "high-dose" omeprazole therapy (up to 80 mg daily), administered in divided doses, may be required to adequately suppress 24-hour acid secretion. Recently it has been shown that high-dose omeprazole therapy (40 mg twice daily) for seven days may be used empirically as a diagnostic tool (the "omeprazole test" ), demonstrating a sensitivity of 83.3 percent.[34] In this test, if a patient's symptoms resolve following high-dose omeprazole therapy, the response suggests that gastroesophageal reflux disease is the cause of the symptoms. Otherwise, an alternate diagnosis should be considered.

At a dosage of 30 mg daily, lansoprazole (Prevacid), a newly developed proton pump inhibitor, is more effective than standard dosages of [H.sub.2] blockers in promoting healing of gastroesophageal reflux disease.[35] Although as effective as omeprazole in equivalent doses, lansoprazole may provide earlier symptom relief.[34] In standard dosages, both proton pump inhibitors appear to be more cost effective than [H.sub.2] blockers for long-term treatment.[3]

The proton pump inhibitors should be considered for treatment of gastroesophageal reflux disease in patients who are resistant to standard treatment with [H.sub.2] blockers. Side effects are minimal and, although much emphasis was placed initially on carcinogenic effects on the stomach during long-term therapy, no reports currently indicate such a complication in humans.

Maintenance Therapy

Most patients with gastroesophageal reflux disease remain symptomatic for years and usually continue taking medication, either on a regular basis or as needed. Patients with more significant disease are particularly prone to early relapse after discontinuing medical treatment, regardless of the therapy.[29] Maintenance therapy with lower dosages of [H.sub.2] blockers (cimetidine at 300 to 1,200 mg daily, ranitidine at 150 to 300 mg daily or famotidine at 20 to 40 mg daily) to prevent recurrence is generally disappointing.[13] Furthermore, patients with severe disease usually relapse even with high-dose [H.sub.2] blocker maintenance therapy.[27] However, several studies report endoscopic relapse rates of 25 to 34 percent over 12 to 24 months of maintenance therapy with omeprazole at 20 mg daily.[36,37]

In a study of omeprazole at 20 mg daily and ranitidine at 150 mg twice daily for maintenance therapy, 12-month relapse rates of 32 percent and 90 percent, respectively, were reported.[38] Most patients who reportedly relapsed with omeprazole at 20 mg daily rehealed with a dosage of 40 mg daily.

When used as maintenance therapy, cisapride has also been demonstrated to significantly increase symptomatic and endoscopic remission rates compared with placebo.[39] However, efficacy is unimpressive in patients with severe esophagitis before healing. Studies comparing cisapride with acid-suppressing agents as maintenance therapy have not been reported; however, a combination of cisapride and omeprazole seems to provide more effective maintenance therapy than omeprazole alone.(40]

Cost Considerations

The retail cost of a 30-day supply of omeprazole at 20 mg daily is slightly higher than the cost for standard doses of the [H.sub.2] blockers (Table 3). One researcher[41] hypothesized that the cost of overall medical care for gastroesophageal reflux disease with esophagitis after failure of phase 1 therapy would actually be significantly less with omeprazole than with ranitidine because of greater clinical efficacy, fewer complications and a reduced need for surgical intervention. Indeed, a prospective study randomizing patients with esophagitis and peptic stricture to treatment with omeprazole at 20 mg daily, ranitidine at 150 mg twice daily or famotidine at 20 mg twice daily reported a cost reduction with omeprazole therapy that was attributed to a decreased need for repeated esophageal bougienage.[42]

[TABULAR DATA 3 OMITTED]

Surgical Therapy

Long-term efficacy of antireflux surgery can be achieved in more than 80 percent of patients followed for an average of 6.6 years after Nissen fundoplication.(43) A Veterans Affairs' cooperative trial(44) compared medical and surgical therapies for complicated gastroesophageal reflux disease and concluded that surgery was more effective at one year of follow-up. Medical therapy was administered in a stepwise combination fashion with antacids, standard-dose ranitidine, sucralfate and metoclopramide.

Other studies have demonstrated that surgery confers better clinical results than [H.sub.2] blocker therapy in patients with gastroesophageal reflux disease-related asthma.[45] Trials comparing surgery and optimal medical management with a proton pump inhibitor have not been performed, but a cost-effectiveness analysis suggests that, in younger patients, surgery is advantageous when compared with a medical strategy that includes omeprazole.[46]

Although the availability of potent acid inhibitors has limited the use of surgery in patients with gastroesophageal reflux disease, the recent introduction of laparoscopic Nissen fundoplication has shifted attention back to surgical management. However, long-term outcome studies are still unavailable. Surgery should be considered in patients with severe complications, in those with refractory disease and in young adults with disabling symptoms who would require long-term aggressive medical management.

RONNIE FASS, M.D. is assistant professor of medicine at the University of Arizona College of Medicine and director of &e Gastrointestinal Motility Laboratory at the Tucson Veterans Affairs Medical Center. Dr. Fass graduated from Ben Gurion University, Israel, and was chief resident in internal medicine at the University of Arizona Medical Center. He completed a fellowship in gastroenterology at the University of California, Los Angeles, School of Medicine.

LEE J. HIXSON, M.D. is currently in private practice in St. George, Utah Dr. Hixson graduated from the University of Utah, where he also completed a residency in internal medicine. Dr. Hixson completed a fellowship in gastroenterology at the University of Arizona Medical Center.

MICHAEL L. CICCOLO, M.D. is currently a fellow in cardiothoracic surgery at the University of Southern California School of Medicine, Los Angeles. After graduating from the University of Iowa College of Medicine, Iowa City, Dr. Ciccolo completed a surgical residency at the University of Arizona Medical Center.

PAUL GORDON, M.D. is associate professor and co-head of the Department of Family and Community Medicine at the University of Arizona School of Medicine. Dr. Gordon graduated from Mount Sinai School of Medicine of the City University of New York, N.Y., and completed a family medicine residency at the University of Rochester (N.Y.) School of Medicine and Dentistry. He also completed a faculty development fellowship at the University of Arizona Medical Center

GLENN HUNTER, M.D. is professor of surgery at the University of Arizona Medical Center. He graduated from the University of Capetown, South Africa, and completed a residency and a fellowship in general and vascular surgery at the University of Arizona Medical Center.

WILLIAM RAPPAPORT, M.D. is associate professor of surgery at the University of Arizona College of Medicine. After graduating from the University of Miami (Fla.) School of Medicine, he completed residencies in pediatrics at Mount Sinai School of Medicine of the City University of New York, in general surgery at the University of Cincinnati (Ohio) College of Medicine, and in plastic surgery at the University of Oklahoma College of Medicine, Oklahoma City